During the last two and a half decades, our laboratory has been actively searching for the methods to reduce myocardial ischemic reperfusion injury during ischemic arrest. Unfortunately, many of the results, not only from our laboratory, but also from most of the laboratories, could not be translated for human patients, as it has become apparent from the failure of clinical trials. During the current funding period, we searched for the methods of healing or repairing of the heart already subjected to ischemia/reperfusion. As a result, we found that ischemic myocardium initially attempts to protect itself by a process known as autophagy. The cardiomyocytes undergoes apoptotic cell death followed by necrosis only when the survival strategies by autophagy fail. Based on our observation, we now propose to enhance heart's ability to induce autophagy at the basal level through physiological means. Our preliminary studies document that autophagy (basal) prior to ischemia or during ischemia is always beneficial to the heart while autophagy during reperfusion (pharmacological autophagy) can be either beneficial or detrimental depending on the situation. We plan to test our hypothesis by addressing five Specific Aims: i) by inducing physiological autophagy prior to ischemia; ii) by enhancing autophagy genes such as Atg and beclin through gene therapy; iii) by inducing autophagy by manipulation of endoplasmic rteticulum stress; iv) by inducing controlled autophagy by redox regulation; and v) by carefully monitoring autophagy mediated conversion of death signal into a survival signal by studying upregulation or downregulation of the genes/proteins of the death vs. survival signaling pathways including classIII PI-3 kinase, bcl-2, NFkB, Sirt, and AMPK. Since autophagy is a nuturl phenomenon by which cells clear unwanted damaged proteins in order to survive, it is our hope that the strategies to hance autophagy at the basal level should enhance heart's ability to harness the protective means by the way of adaptation to the ischemic stress. PUBLIC HEALTH RELEVANCE: Cardiovascular diseases are the major cause for the morbidity and mortality in the developed countries. Ischemic heart disease represent the major cardiovascular related problems. Straitegies to reduce ischemic injury should improve the heart health leading to the reduction of death due to heart diseases.